- New catalytic route for the synthesis of an optically active tetralone-derived amine for rotigotine
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Rotigotine is a launched drug for the treatment of Parkinson's disease and restless legs syndrome. The key steps of an alternative route for the synthesis of rotigotine have been demonstrated. Formation of a prochiral enamide, asymmetric hydrogenation of the enamide with high enantioselectivity, and reduction of the resulting amide to an amine have been proved to work successfully. The best conditions screened to date for the asymmetric hydrogenation of enamide 9 to amide 10 were with [(RuCl((R)-T-BINAP))2(μ-Cl)3][NH2Me2] at 25 bar H2 and 30 °C (500:1 S/C ratio, 99% conversion, 91% ee S). Reduction of amide 10 to amine 5 was best achieved with Red-Al giving 95% conversion.
- Cobley, Christopher J.,Evans, George,Fanjul, Tamara,Simmonds, Shaun,Woods, Amy
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- Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT
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The optically pure enantiomers of the potential atypical antipsychotic agents 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 5) and 5-methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-n-propylamino}tetralin [5-OMe-(2,6-di-OMe)-BPAT
- Homan, Evert J.,Copinga, Swier,Unelius, Lena,Jackson, David M.,Wikstroem, Hkan V.,Grol, Cor J.
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- Preparation method of rotigotine
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The invention relates to the technical field of medicine preparation, and discloses a preparation method of rotigotine, which comprises the following steps: by taking 5-methoxy-2-tetralone as an initial raw material, reacting with R-alpha-methylbenzylamine, performing debenzylation reduction and S-mandelic acid chiral resolution, then reacting with a propionyl chloride reagent to generate an amide compound, and then reducing by a sodium borohydride reagent to obtain the rotigotine; and finally, reacting with 2-(thiophene-2-yl) 2-nitric acid benzene sulfonic acid ethyl ester to obtain the rotigotine. The preparation process route is as follows: the rotigotine is mild in preparation condition, simple and convenient to operate, relatively high in yield of key intermediates, high in optical purity and easy for industrial large-scale production, and has a very good application prospect.
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Paragraph 0064-0066
(2021/08/11)
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- Synthesis of Pharmaceutically Relevant 2-Aminotetralin and 3-Aminochroman Derivatives via Enzymatic Reductive Amination
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2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.
- Citoler, Joan,Harawa, Vanessa,Marshall, James R.,Bevinakatti, Han,Finnigan, James D.,Charnock, Simon J.,Turner, Nicholas J.
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supporting information
p. 24456 - 24460
(2021/10/19)
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- Preparation method for rotigotine
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The invention discloses a preparation method for rotigotine. The preparation method includes the following steps: S1. performing an amination reduction reaction on a 5-methoxy-2-tetralone solution, tert-butanesulfinamide, a catalyst, and sodium borohydride to obtain a substance A; S2. performing an alkylation reaction on a solution of the substance A, bromopropane, and a basic catalyst to obtain asubstance B; S3. reacting the substance B with a hydrochloric acid methanol solution to obtain a substance C; S4. performing a reaction on the substance C, 2-(2-bromoethyl)thiophene, potassium carbonate, and N,N-dimethylformamide to obtain a substance D; and S5. reacting acetic acid with hydrogen bromide to obtain the rotigotine. The preparation method is simple in operation, is high in yield, ismild in reaction condition, is green and environmentally friendly, is high in purity of the prepared rotigotine, and is suitable for large-scale industrial production.
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Paragraph 0061; 0170; 0194-0199; 0218
(2019/04/17)
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- Enantioselective Synthesis of β-Aminotetralins via Chiral Phosphoric Acid-catalyzed Reductive Amination of β-Tetralones
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A new protocol for the synthesis of chiral β-aminotetralins has been developed via chiral phosphoric acid-catalyzed asymmetric reductive amination of β-tetralones using a Hantzsch ester as an organic hydride donor. Various chiral β-aminotetralins were obtained in good yields with good to high enantioselectivities. Furthermore, the utility of our new protocol was successfully demonstrated in the enantioselective synthesis of rotigotine. (Figure presented.).
- Park, Do Young,Kim, Kyung-Hee,Cheon, Cheol-Hong
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supporting information
p. 462 - 467
(2017/12/07)
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- PROCESSES FOR THE PREPARATION OF ROTIGOTINE AND INTERMEDIATES THEREOF
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The present invention provides processes for the preparation of a compound of Formula 2 or a salt thereof, wherein R1 is selected from the group consisting of H, C1-C3 alkyl, and C(0)R3; R3 is selected from the group consisting of C1-C6 alkyl, C6-C10aryl and C7-C20 arylalkyl; the carbon atom marked with "*" is racemic, enantiomerically enriched in the (R)-configuration, or enantiomerically enriched in the (S)-configuration. Also provided are intermediate compounds of the processes.
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- luo Ti gastrodia tuber of a kind of preparation method
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The invention discloses a preparation method of rotigotine, and belongs to the technical field of medicine synthesis. According to the method, 5-methoxy-2-tetralone is used as a raw material for amination, asymmetric reduction, halogenation and methoxyl group removal four step reaction for synthesis of chiral rotigotine {(-)-(S)-2-(N-propyl-N-(2-(2-thiophene) ethyl] amino]-5-hydroxy-1, 2, 3, 4-tetralin}. According to the method, a simplex stereoscopic structural compound is synthesized by stereo selective chemical reaction, in the asymmetric reduction process, hantzsch ester 1, 4-dihydropyridine (HEH) is used as a reducing agent, and chiral phosphoric acid is used as a catalyst to synthesize an important intermediate (S)-2-(N-n-propyl) amido-5-methoxy tetralin (II) with a simplex stereoscopic structure, the use of a chiral reagent for splitting to obtain the simplex stereoscopic structural compound is avoided, the synthesis procedure is shortened, the yield is improveds, and the method is favorable for industrialized production.
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Paragraph 0021; 0036; 0038
(2017/02/24)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGIC DISEASES
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Provided are compounds, pharmaceutical acceptable salts, polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising the compounds may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup or injection, and may be used for the treatment of neurologic diseases, such as depression, Alzheimer's disease, multiple sclerosis, Batten disease, Parkinson's disease and restless legs syndrome.
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Paragraph 0099; 00100
(2013/12/03)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE (S)-(-)-2-(N-PROPYLAMINO)-5-METHOXYTETRALINE AND (S)-(-)-2-(N-PROPYLAMINO)-5-HYDROXYTETRALINE COMPOUNDS
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The present invention describes a novel process for the preparation of optically active (S)-(?)-2-(N-propylamino)-5-methoxytetraline and (S)-(?)-2-(N-propylamino)-5-hydroxytetraline compounds based on the optical resolution of mixtures of the enantiomers of 2-(N-propylamino)-5-methoxytetraline and 2-(N-propylamino)-5-hydroxytetraline respectively. This process comprises (a) reacting a mixture of the enantiomers of said compounds with an optically active organic acid to form diastereoisomeric salts and separating the salts by crystallization. Said compounds are useful in the preparation of (6S)-(?)-5,6,7,8-tetrahydro-6-[propyl-(2-thienyl)ethyl]amino-1-naphthol (Rotigotine). Rotigotine is a dopamine agonist and is indicated for the treatment of Parkinson's disease.
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Page/Page column 3
(2011/07/06)
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- Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl) ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson's disease anima
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Here we report structure - activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were
- Ghosh, Balaram,Antonio, Tamara,Zhen, Juan,Kharkar, Prashant,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 1023 - 1037
(2010/08/06)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE (S)-(-)-2-(N-PROPYLAMINO)-5-METHOXYTETRALINE AND (S)-(-)-2-(N-PROPYLAMINO)-5-HYDROXYTETRALINE COMPOUNDS
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The present invention describes a novel process for the preparation of optically active (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5- hydroxytetraline compounds based on the optical resolution of mixtures of the enantiomers of 2-(N-propylamino)-5-methoxytetraline and 2-(N-propylamino)-5- hydroxytetraline respectively. This process comprises (a) reacting a mixture of the enantiomers of said compounds with an optically active organic acid to form diastereoisomeric salts and separating the salts by crystallization. Said compounds are useful in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[propyl-(2- thienyl)ethyl]amino-1 -naphthol (Rotigotine). Rotigotine is a dopamine agonist and is indicated for the treatment of Parkinson's disease.
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Page/Page column 7
(2010/04/30)
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- Synthesis and evaluation of pharmacological and pharmacokinetic properties of monopropyl analogs of 5-, 7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2- aminotetralins: Central dopamine and serotonin receptor activity
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In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8- triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R- (+)-6 was found to be a potent and selective 5-HT(1A) (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 ± 1.1%) appeared to be slightly lower than that of 2 (11.2 ± 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.
- Sonesson,Barf,Nilsson,Dijkstra,Carlsson,Svensson,Smith,Martin,Duncan,King,Wikstrom
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p. 1319 - 1329
(2007/10/02)
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- Fluorescent Probes for Dopamine Receptors: Synthesis and Characterization of Fluorescein and 7-Nitrobenz-2-oxa-1,3-diazol-4-yl Conjugates of D-1 and D-2 Receptor Ligands
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Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors.Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl)derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace SCH 23390 and 3H)spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis).The fluorescein derivatives of PPHT andSKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of parent ligands.The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands.The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues.In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor.These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively.The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
- Bakthavachalam, Venkatesalu,Baindur, Nandkishore,Madras, Bertha K.,Neumeyer, John L.
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p. 3235 - 3241
(2007/10/02)
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- Structure-Activity Relationships of Dopaminergic 5-Hydroxy-2-aminotetralin Derivatives with Functionalized N-Alkyl Substituents
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5-Hydroxy-2-aminotetralin derivatives in which one N-alkyl substituent carries a functional group have been prepared and their dopaminergic activities compared with those of 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) and known ergolines.Several members of the series demonstrated high affinities in dopamine (DA) receptor binding and DA agonist properties in the rotational behavior model in the range of known potent ergolines.The results suggests that the accessory binding site for the larger N-alkyl substituent of the 5-hydroxy-2-aminotetralins can accommodate various neutral and bulky functionalities and is probably identical with the site(s) to which the 8-substituents of the ergolines bind.
- Seiler, Max P.,Stoll, Andre P.,Closse, Annemarie,Frick, Willy,Jaton, Annelise,Vigouret, Jean-Marie
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p. 912 - 917
(2007/10/02)
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- Resolved Monophenolic 2-Aminotetralins and 1,2,3,4,4a,5,6,10b-Octahydrobenzoquinolines: Structural and Stereochemical Cosiderations for Centrally Acting Pre- and Postsynaptic Dopamine-Receptor Agonists
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A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors.The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hy
- Wikstroem, Hakan,Andersson, Bengt,Sanchez, Domingo,Lindberg, Per,Arvidsson, Lars-Erik,et al.
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p. 215 - 225
(2007/10/02)
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